Age-related macular degeneration (AMD) is one of the leading causes of vision irreversible damage in people over the age of 50 years. AMD is clinically divided into two types as “dry” and “wet”. The wet form of AMD may develop rapidly and often results in blindness. The pathological changes of the disease may cause severe visual impairment. The manifestations of AMD may include, but is not limited to retinal pigment epithelial cells (RPE) dysfunction and choroidal neovascularization (CNV) in the macular area. Fluid leakage, RPE or neural epithelial detachment and bleeding from ruptured blood vessels can occur in severe cases. It has been found that many cellular factors play important roles in regulation in CNV generation, among which may include but are not limited to vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR), platelet-derived growth factor (PDGF), hypoxia inducible factor (HIF), angiopoietin (Ang) and other cytokines, mitogen-activated protein kinases (MAPK) and others.
One currently approved treatment for wet AMD is Lucentis®. Lucentis® is an anti-angiogenesis agent and targets all isoforms of Vascular Endothelial Growth Factor (VEGF). Clinical studies have shown improved or stable vision in approximately 95% of patients administered Lucentis®, compared to approximately 60% of the patients who received sham treatment. Although Lucentis® is the first approved agent to improve vision it requires intravitreal administrations every 4 weeks for optimal visual benefit. Eylea® is another VEGF inhibitor that has been approved to treat wet AMD. Eylea® also requires frequent intravitreal injections every 4-8 weeks for optimal visual benefit. Intravitreal routes of administration may increase risks for serious complications such as infectious endophthalmitis and retinal detachment, for which cumulative risk increases with repeated administrations. Increased intraocular pressure, traumatic cataract, and retinal tears have also been reported. Finally, with a treatment that is delivered by an ophthalmologist, treatment frequency determines the burden to the patient, physician, and health system in general and to the extent possible should be reduced. The limitations of currently available therapy for CNV secondary to AMD have created a need in the art for alternative approaches which address the high frequency of treatments required and the invasiveness of the treatment procedure. Neovascularization involving VEGF elevation can also lead to other ocular pathologies, such as diabetic retinopathy, diabetic macular edema (DME), and retinal vein occlusions (RVO). These diseases lead to retinal neovascularization and vision loss. VEGF inhibitors such as Lucentis® have demonstrated efficacy in DME and RVO, and, like with wet AMD, require frequent intravitreal administration in order to maintain benefit.